CA2756099A1 - Nicotinamide derivatives, preparation thereof, and therapeutic use thereof as anticancer drugs - Google Patents

Abstract

The present invention relates to nicotinamide derivatives of formula (I), the compositions containing them and their therapeutic application, especially as anticancer agents. The invention also relates to the process for the preparation of these compounds as well as to some of the intermediate products.

Description

WO 2010/10912

2 PCT / FR2010 / 050511 NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION
THERAPY AS ANTICANCER

The present invention relates to nicotinamide derivatives, compositions containing and their application in therapy, especially as anticancer.
The invention also relates to the process for preparing these compounds and to some of intermediate products.

[The prior art]
The international application WO 2005/051366 describes compounds of formula general (A) CH2) A = ~ .A ~ ~ i O
(Y2). R5 (A) wherein Z represents a phenyl or indanyl group and not a group pyridinyl.

International Application WO 2007/016538 describes compounds of formula General (B):
O OH
R¾
s YEN 2Rs r - T
R ~

H (B) wherein Q may be R13-NR12-C (= O) -, R13 may be a group 2-,

3- or 4-pyridinyl, R4 and R5 representing a hydrogen atom, a group alkyl, alkoxy, -OH, -CF3 or -CN. These compounds are used in the treatment of obesity.
[Description of the invention]
Definitions used In the context of the present invention, the following terms mean:
= halogen atom: a fluorine, chlorine, bromine or iodine atom;
= alkyl group: a saturated aliphatic hydrocarbon group comprising from 1 to 6 atoms carbon (advantageously from 1 to 4 carbon atoms) obtained by removing a hydrogen atom of an alkane. The alkyl group can be linear or branched.
As examples include methyl, ethyl, propyl, isopropyl, butyl, iso butyl, tert-butyl, pentyl, 2,2-dimethylpropyl, hexyl;
= alkoxy group: -O-alkyl group, where the alkyl group is as defined above;
= cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 atoms of carbon, all carbon atoms being involved in the ring structure.
As examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
= heterocycloalkyl group: a cycloalkyl group comprising at least one hetero (O, S, N) engaged in the ring and connected to the carbon atoms forming the cycle. As examples include pyrrolidinyl, piperidinyl, piperazinyl or N- (C1-C4) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxo thiomorpholinyl.

According to a first aspect, the subject of the present invention is a compound of formula (I) Z'-NHR2 z oy 3 IZ ~ NRIR-1 5 to L ~ N 4 6 H 5 (F) x Rat 5 z N (I) in which = Z and Z 'represent N or CH;
= x is an integer equal to 1 or 2, representing the number of fluorine atom (s) attached to central phenyl nucleus;
= L represents a group -CH = CH- or - (CH2) nNH- in which the NH group is attached to at C = O and n is an integer of 0, 1 or 2;
R1 represents a hydrogen atom, a (C1-C6) alkyl group, (C3-C6) cycloalkyl, phenyl;
R'1 represents a hydrogen atom or a (C1-C6) alkyl group;
= R2 represents:
a (C3-C6) cycloalkyl group;
a (C1-C6) alkyl group, optionally substituted with:
one or more hydroxyl or (C1-C4) alkoxy groups;
o a group -NRaRb in which Ra and Rb independently represent one of the other a hydrogen atom or a (C1-C6) alkyl group or together with the nitrogen atom to which they are attached a (C4-C6) heterocycloalkyl group optionally comprising in the cycle the group -S (O) q with q = 0, 1 or 2 or the -NH- or -N (C1-C4) alkyl- and being optionally substituted by one or more substituent (s), which are identical or different from each other when there are several, chosen from among group -OH ; (C1-C4) alkoxy or (C1-C4) alkyl;
R3 represents at least one substituent of the pyridine ring chosen from atom of hydrogen or fluorine, a (C1-C4) alkyl group or -NRcRd in which Rc and Rd represent a hydrogen atom or a (C1-C4) alkyl group;

R1 represents a hydrogen atom, a (C1-C6) alkyl group, (C3-C6) cycloalkyl, by cyclopropyl example, a phenyl group. R'1 represents a hydrogen atom or one (C1-C6) alkyl group. More particularly, R'1 represents an atom hydrogen. We will be able to choose R1 and / or R'1 from those described in Table I.

R2 represents:
a (C3-C6) cycloalkyl group, such as, for example, the cyclopropyl group or cyclopentyl;
a (C1-C6) alkyl group, optionally substituted with:
one or more -OH or (C1-C4) alkoxy group (s), for example methoxy;
o a group -NRaRb in which Ra and Rb independently represent one of the other a hydrogen atom or a (C1-C6) alkyl group or together with the nitrogen atom to which they are attached (C4-C6) heterocycloalkyl comprising possibly in the cycle the group -S (O) q with q = 0, 1 or 2 or the group -NH-or -N (C1-C4) alkyl-. Preferably, q = 1 or 2.

The heterocycloalkyl group formed by Ra and Rb can be, for example, the group pyrrolidinyl (), piperidinyl (), piperazinyl (HN) or N- (C1-C4) alkyl-piperazinyl NN ~
Alk-N ~ G
(), especially N-methyl-piperazinyl, azepanyl (), thiomorpholinyl r_ ~ N s g ~ 0 SI_ ~ j 11 ~ _j ), 1-oxo-thiomorpholinyl (), 1,1-dioxothiomorpholinyl ().

4 The heterocycloalkyl group formed by Ra and Rb may be optionally substituted by one or several substituents, identical or different from each other when there are several, chosen from: -OH; (C1-C4) alkoxy: for example methoxy; (C1-C4) alkyl:
for example methyl. Thus, the substituted heterocycloalkyl may be the 3-hydroxypiperidinyl N ~ N

(OH or 4-hydroxy-piperidinyl (HO 4-methoxy-piperidinyl (Meo ))) NLN
cis-3,5-dimethyl-piperidinyl (), cis-2,6-dimethyl-piperidinyl ().
R2 can be selected from one of those described in Table I.

The pyridine ring may comprise from 1 to 4 substituents R 3 selected from one of atom of hydrogen or fluorine, a (C1-C4) alkyl group or -NRcRd in which Rc and Rd represent a hydrogen atom or a (C1-C4) alkyl group. We will be able to choose R3 from those described in Table I. Preferably, R3 is in position 5 and / or 6 on the kernel pyridine. Preferably, the number of substituents R3 is equal to 1 and / or R3 is in position 5 or 6 on the pyridine ring as shown below:

position 6 position 5 R3 is even more preferentially in position 6. Preferably, R3 represents an atom of hydrogen or -NH2.

L represents a group -CH = CH- or - (CH2) nNH- in which the NH group is attached to the C = O and n is an integer equal to 0, 1 or 2. Preferably, n is equal to 1. L may to be one of those described in Table I. It is also preferred, in the case where L represents the group -CH = CH-, E isomers rather than Z isomers.

Z and Z 'represent N or CH. For example, Z and Z 'can represent respectively N and CH; CH and CH or N and N:

/ CONHR2 OCNR: ixN II, NR NR R 'R R' C, C2 C3 x is an integer of 1 or 2, representing the number of fluorine atom (s) attached to the kernel central phenyl. More particularly, x is 1.

We distinguish the subgroup of formula (l ') z o 3 N NR1R'1 at CHZNH H 5 (F) x

R3 N (I ') wherein R1, R'1, R2, R3 and x are as previously defined.
There is a subgroup of formula (I ") z o 3 NL NHRI
CHZNH H 5 (F) x R3 N (I ") in which R1 represents a (C1-C4) alkyl group, R2 represents a group (C1-C6) alkyl optionally substituted with the group -NRaRb in which Ra and Rb form together with the nitrogen atom to which they are connected the (C4-C6) heterocycloalkyl group comprising possibly in the cycle the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C1-C4) alkyl and R3 and x being as defined above. More especially, x is 1. More more particularly, x is 1 and the fluorine atom is in the 3-position.

Among the compounds that are the subject of the invention, mention may be made of those of Table I.

The compounds of the invention, including the exemplified compounds, can exist in the state of bases or addition salts with acids. Such addition salts make also part of the invention. These salts are advantageously prepared with acids pharmaceutically acceptable but the salts of other useful acids, for example, for the purification or the isolation of the compounds are also part of the invention. Compounds according to the invention may also exist in the form of hydrates or solvates, know under form of associations or combinations with one or more water molecules or with a solvent. Such hydrates and solvates are also part of the invention.

6 The compounds may have one or more asymmetric carbon atoms.
They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures are part of the invention.
According to the present invention, the N-oxides of compounds containing an amine or an atom nitrogen are also part of the invention.

According to a second aspect, the subject of the invention is the process for the preparation of composed of the invention as well as some of the reaction intermediates.
Preparation of the compounds of formula (I) or (I) for which L = - (CH2 2) NH-These compounds can be prepared according to one of the following Schemes 1-3.

Diagram 1 OK O
OHO B.OK 'Z'i, NHR2 NHRZ CNxNe [Pd] C 1 z R R'1 Hal NR R + Rs Jn HH (F) x N i Z
1 1 Rs -Q4 ~ HH (F) x P1 P2 (~) Diagram 1 A Suzuki coupling of P1 and P2 is carried out. Hal represents an atom halogen (chlorine, bromine, iodine). The coupling is carried out in the presence of a complex of palladium (to the oxidation state (0) or (II)) in basic medium. The complex can be by example Pd (PPh3) 4, PdCl2 (PPh3) 2, Pd (OAc) 2, PdCl2 (dppf) or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II). The most complex frequently used are palladium complexes (0). The base can be for example K2CO3, NaHCO3, Et3N, K3PO4, Ba (OH) 2, NaOH, KF, CsF, Cs2CO3 ... Coupling can be conducted in one mixture of an ethereal solvent and an alcohol, for example a mixture dimethoxyethane (DME) / ethanol; it can also be a toluene / water mixture. Temperature is included between 50 and 120 C. The duration of the reaction can in some cases be long (see 1.3).

More details on Suzuki's coupling, conditions operative as well as on the palladium complexes usable in: N.Miyaura and A.Suzuki, Chem.
Rev. 1995 95, 2457-2483; A.Suzuki in "Metal-catalyzed cross-coupling reactions";
Diederich, F .;
Stang, PJ Eds. Wiley-VCH: Weinhein, Germany, 1998, chap. 2, 49-97; Littke, A. and Fu, G.,

7 Angew. Chem. Int., Ed. 1999, 38, 3387-3388 and Chemler, SR
Angew.Chem.Int.Ed. 2001, 40, 4544-4568.

K and K 'represent a hydrogen atom, an alkyl or aryl group, possibly connected between them to form together with the boron atom and the two atoms of oxygen a cycle from 5 to 7 chain members optionally substituted by at least one group (C1-C4) alkyl or to which optionally is attached to two consecutive carbon atoms of said cycle a group phenyl. For example, one of the following groups can be used:

OH OOOO
3CB-OH 3tB0B0 3CB ~ 0 0 Figure 2 O OK O
Y
NHR2 B OK '[Pd] Z'iNHR2 H -Z ' Hal ~ z NRR '+ H2N (F) I \ ZR R'1 + R CiivH2 C-011 X HzN
pp P3 (F) X P4 PS O
Z ', NHR 2 C xN R1R
Z
RHH (F) X
(I) According to Scheme 2, a Suzuki coupling (see above) is made between Pl and P3 for obtain P4, then react P4 with P5 in the presence of an agent allowing to introduce the "C = O" motif (for example phosgene, triphosgene or N, N'-disuccinimidyl DSC). The reaction to introduce "C = O" is conducted preferably in the presence of a base such as for example triethylamine and at a temperature included between -5 C and room temperature. The solvent may be THF. See ex.
1.4.

Figure 3 COOH O

HO Zlz NR 'Z'iY -, -Qq N R2NH2 HOI -R'1 Rs j H _ C x N Ri (F) X Rs l H
P6 (F) X
(I) According to Scheme 3, the compound of formula (I) is obtained by a reaction from amidation to from P6 and the amine R2NH2 or a salt of this amine, for example hydrochloride (see ex.3.2). The amidification can be carried out advantageously in the presence of a activator

8 of acid (also called coupling agent) as for example benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS N 56602-33-6, see also B.Castro., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably in the presence of a base (such as triethylamine) at temperature ambient, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
P6 is obtained by a Suzuki coupling reaction between P2 and the compound P8 of formula:

Z: oh I ~
Hal z NRlR'l P8 according to a scheme similar to Scheme 1.
preparation of Pl ooo ZR, R ', NH ~ ^
Z 'OH Z' \ OH RZNHZ Z.
NHRZ Hal Hal Hal z NR, R ', Hal' NR, R ', P7 P8 Pl Figure 4 P8 is obtained from P7 acid by monosubstitution with an amine of formula R1R'1NH.
In the case of an aliphatic amine, the reaction can be carried out ambient temperature and in a protic solvent such as an alcohol or water or in a solvent aprotic such as the THF. In the case of aniline, a strong base such as for example the LiHMDS
(((CH3) 3Si) 2NLi) and the reaction is conducted under heat. Monosubstitution is described in pages 14-15 of FR 2917412 in the case where Z = N and Z '= CH but can be applied to others Z / Z '.
See also ex.1.1.
Z = N, Z '= CH: P7 is a 2,6-dihalogenonicotinic acid, for example the acid 2,6 dichloronicotinic which is commercial (see Example 1.1);
Z = N, Z '= N: P7 is a 2,4-dihalogenopyrimidine carboxylic acid, by example the acid 2,4-dichloropyrimidine carboxylic acid which is commercial (CAS N 37131-89-8);
Z = CH, Z '= CH: P7 is a 2,4-dihalogenobenzoic acid, for example the acid 2,4 dichlorobenzoic acid which is commercial (CAS N 50-84-0).

In the case where Z and Z 'are both N and Hal represents an atom chlorine, P8 can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4-

9 dichloro-, ethyl ester:

N o R, R ', NH ~ OEt LiOH.H2O OH
CI N CI
THFCI N NRlR'l CI IN NRlR'l CAS: 51940-64-8 Pe Figure 5 Scheme 5 using an ester function subsequently converted to an acid function applies also in the case where Z = N and Z '= CH: see the conditions in Chem.Pharm.Bull. 2000 48 (12) 1847-1853 (reactions of Tables 1 and 2).

P1 is obtained from P8 acid by amidification using amine R2NH2 or a salt of this amine, for example the hydrochloride. Amidation can be conducted advantageously in presence of an acid activator (also called coupling agent) as example the benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS N 56602-33-6, see also Castro, B., Dormoy, JR Tetrahedron Letter 1975, 16, 1219).
The reaction is preferably carried out in the presence of a base (such as triethylamine) to ambient temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF). See ex.1.2.

preparation of P3 The compounds P3 for which K and K 'form the following group:
or can be prepared according to the coupling reaction between a bromo-aniline fluorinated and bis (pinacolato) diboron which is described in Figure 2 on page 150-151 of WO
2007/064931: 3-F (4-amino-3-fluorophenylboronic acid pinacol ester, CAS N
819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709);
2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS N 819057-45-9, Boron Molecular, described on page 185 of WO 20071064931); 2-F, 5-F (CAS N 939807-75-7, compound described in page 184 of WO 20071064931); 3-F, 5-F (CAS N 939968-08-8, described on page 182 of WO
2007/064931).

The compounds P3 for which K and K 'represent a hydrogen atom can be prepared from the fluorinated bromoaniline by the reactions described in Tetrahedron Letters 2003, 44, 7719-7722.

P2 preparation The P2 compounds are obtained from the compounds P3 and P5 in the presence of a agent to introduce the "C = O" pattern, according to a reaction as described previously.

R2NH2 compounds Amines R2NH2 are commercial products or already described in Documents published; for example :
= 1- (2-aminoethyl) piperidine: CAS N 27578-60-5, described in Justus Liebigs Annalen der

Chemie 1950, 566, 210-44, marketed by ACROS;
= 1-Piperidinepropanamine: CAS N 3529-08-6, described in Bioorganic & Med.
Chem.Lett.
2006, 16 (7), 1938-1940;
= 1-Piperidinebutanamine: CAS N 74247-30-6, described in Bioorganic & Med.
Chem.Lett.
2006, 16 (7), 1938-1940;
= 4-piperidinol, 1- (2-aminoethyl) -: CAS N 129999-60-6, described in J.Med.Chem.

48 (21), 6690-6695 and on page 17 of WO 2005/061453 (ref.ex.10);
= 3-piperidinol, 1- (2-aminoethyl) -: CAS No. 847499-95-0, described in J.Med.Chem.

48 (21), 6690-6695 and on page 16 of WO 2005/061453 (ref.ex.8);
= 2- (4-methoxy-1-piperidinyl) ethylamine: CAS N 911300-69-1, described in J. Med.
2007, 50 (20), 4818-4831;
= pyrrolidineethanamine: CAS N 7154-73-6, described in Anales de Quimica 1974, 70 (9-10) 733-737, marketed by International Laboratory Ltd., 1067 Sneath Ln, San Bruno, CA94066, USA;
= 1-piperazineethanamine: CAS N 140-31-8, described in EP 151232;
= azepan-1-ylethylamine: CAS N 51388-00-2, described in Anales de Quimica 1974, 70 (9-10) 733-737;
= 2- (1,1-dioxothiomorpholin-4-yl) ethylamine: CAS N 89937-52-0, marketed by Intern.
Lab. Ltd;
= N- (2-aminoethyl) thiamorpholine-1-oxide: CAS N 1017791-77-3, marketed by Sinova Inc. 3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.

A method for obtaining compounds for which R2 represents a group (C1-C6) alkyl substituted by the group -NRaRb in which Ra and Rb together with the nitrogen atom to which they are connected the heterocycloalkyl (C4-C6) group comprising possibly in the cycle the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C1-C4) alkyl is described on

11 Figure 6 which is inspired by scheme 3 of Bioorg. Med. Chem. 2007, 15, 365-373 or Figure 2 of Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381:
oo based N (C, -C6) Alk-Br + NHRaRb C_-N- (C1-C6) Alk-NRaRb hydrazine OO
NH 1- (Cl-C6) AIk-NRaRb Figure 6 Another method described in Figure 6 'is based on Figure 2 of Bioorg.
Med. Chem.
Lett. 2006, 16, 1938-1940:
hydrogenation base NC- (C1-C5) Alk-Br + NHRaRb-NC- (C1-C5) Alk-NRaRb-NH2 (CI-C6) Alk-NRaRb Figure 6 P5 compounds P5 can be either commercial or prepared according to known methods of the skilled person.
For example, the hydrogenation of the cyano compound can be used to obtain P5 with n = 1 RR
P5 with n = 1 Figure 7 The hydrogenation conditions can be those described in ex.19 and 20 of WO
00/46179 or in Synlett 2001, 10, 1623-1625.

The compounds 3-picolylamine (CAS N 3731-52-0), 3- (2-aminoethyl) pyridine (CAS N

24-4), 2-amino-5-aminomethylpyridine (CAS N 156973-09-0), 2-methyl-5-aminomethylpyridine (CAS N 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS N

45-9), 2- (BOC-amino) -5-aminomethyl-pyridine (CAS N 187237-37-2), 2.5-diaminopyridine (CAS N 4318-76-7) are commercial products. 2-amino-5-aminomethylpyridine can also be prepared according to EP 0607804. 5-Aminomethyl-2-(dimethylamino) pyridine (CAS
N 354824-17-2) is commercial or can be prepared according to J.Agr.Food Chem.
2008, 56 (1), 204-212. 2-amino-3-methyl-5-aminomethylpyridine (CAS N 187163-76-4) can to be obtained by catalytic hydrogenation of 6-amino-5-methyl-nicotinonitrile compound (CAS

91-3), the amine function being doubly protected by the BOC. hydrogenation catalytic

12 6-methylamino-3-pyridinecarbonitrile (CAS N 261715-36-0) provides access at 2-methylamino-5-aminomethylpyridine.

The preparation of 5-aminomethyl-2- (dimethylamino) pyridine (CAS N 779324-37-7) and from 5-aminomethyl-2- (dimethylamino) pyridine (CAS N 354824-17-2) in the form of hydrochloride is also described on page 106 of WO 2007/044449 (eg 207 and 208).

Preparation of compounds of formula (I) for which L = -CH = CH-These compounds are obtained by an amidification reaction between P4 and the acid P1o or the acyl halide P'10, derived from P1o. Amidation using P1o can to be realized advantageously in the presence of an acid activator such as BOP.

R3 OH R3 Hal P1o P'1 with Hal = F, Br, CI

P1o can be either commercial or prepared according to known methods of the skilled person.
For example, trans-3- (3-pyridyl) acrylic acid is marketed by Sigma-Aldrich. The (6-aminopyridin-3-yl) acrylic acid (CAS N0234098-57-8; compound E: CAS N 167837-43-6) is described in J.Med.Chem. 2002, 45 (15), 3246-3256 (see diagram 4). P1o can be prepared for from bromo aniline and acrylic acid according to the teaching of J. Med. 2002 45 (15), 3246-3256. It is also possible to use a coupling using a bromo aniline and a alkyl acrylate, and then saponify the ester function in acid function (see In this regard, method for preparing the (6-aminopyridin-3-yl) acrylic acid described in paragraph [483] US 2008269220 or [354] EP1726580).

P1o can also be prepared according to J.Org.Chem. 1998, 63, 8785-8789 from the beta corresponding formylpyridine or according to J.Med.Chem. 1989, 32 (3), 583-93 to from the 2-chloro-5-nitro-pyridine. The acyl halide P'1o is obtained by a known reaction of those skilled in the art from P1o acid and an acylating agent such as example SOC12 or (COCI) 2.

13 These compounds can also be prepared according to the following scheme 8:
Figure 8 O

Z. N-R ' P4 + CI NH F R1 Fold O
Z NH-R2, Hal OI i -R ' R3 \
NH (F) R1 (I) According to Scheme 8, P4 is reacted with acryloyl chloride in the presence a base such as for example triethylamine and at a temperature of between 0 C and the ambient temperature to obtain P ,,. The solvent may be the dichloromethane (DCM) (see example 4.1).
Then Põ is reacted with P12 (Hal represents a halogen atom), presence of a palladium complex such as for example Pd (OAc) 2, tri-orthotolylphosphine and a base such as for example diisopropylethylamine. The solvent can to be by example propionitrile. The temperature is between the temperature ambient and the reflux temperature of the solvent.

Protection of the primary or secondary amine function It may be necessary to use at least one of the steps a group protector (PG) in order to protect one or more chemical function (s), including a function primary amine or secondary. For example, when Ra and Rb both represent an atom hydrogen, the amidification of Scheme 3 is carried out using for R2NH2 the compound 2HN- (C1 C6) alkyl-NH-PG, where PG is advantageously BOC (tert-butoxycarbonyl). Of same, when the heterocycloalkyl group formed by Ra and Rb represents the group

14 piperazinyl (HN ~), the -NH- function can be advantageously protected by using 2HN- (C1-C6) alkyl-N N-PG
the following R2NH2 compound, where PG advantageously represents the BOC. Similarly, when R3 represents the group -NH2 or -NHRc, it is possible to protect advantageously the amine function with one or two PG group (s), preferably the BOC or FMOC (9-fluorenylmethyl carbamate). For example, the compound can be used following: (BOC) 2N N, or the following compounds P1o or P'10 NH (FMOC) _ OH NH (FMOC) Hal P10 P'10 with Hal = F, Br, CI

The chemical function (s) is / are then obtained by a step of protection (final or intermediate) whose conditions depend on the nature of the function (s) protected (s) and protective group used. We can refer to Protective groups in T.Greene's Organic Synthesis, Wiley, 4th ed., Isbn = 978-0-471-69754-1, in particular chap.7 with regard to the protective groups of the amine function. In the case of the protection of the functions -NH2 or -NH- by the BOC, the deprotection step is conduct in acid medium using, for example, HCl or trifluoroacetic acid (TFA). We obtain thus, if appropriate, the associated salt (hydrochloride or trifluoroacetate).

Obtaining salts The salts are obtained during the deprotection step described above or well by setting contact of the acid and the compound in its base form.
In the previous schemes, the starting compounds and reagents, when their mode of preparation is not described, are commercially available or described in the litterature, or may be prepared by methods described therein or are known from the skilled person. The skilled person may also be inspired by the conditions operating data in the examples which are described below.

Obtaining N-oxides The N-oxides of the compounds containing an amine or a nitrogen atom are prepared according to methods known to those skilled in the art by reaction of the amine with peracids organic compounds such as peracetic, trifluoroperacetic, performic, perbenzoic acid or its derivatives, such as 3-chloroperbenzoic acid, to temperatures between 0 C and 90 C, preferably at temperatures below 50 vs.

According to a third aspect, the invention relates to a pharmaceutical composition including a Compound as defined above in combination with an excipient pharmaceutically acceptable. The excipient is selected from excipients known usual of the person skilled in the art according to the pharmaceutical form and the mode of administration wish. The method of administration may be for example orally or by intravenous.

According to a fourth aspect, the subject of the invention is a medicinal product which comprises a compound such as previously defined as well as the use of a compound as defined previously, for the manufacture of a medicine. It can be useful to treat a condition pathological, in especially cancer. The drug (as well as a compound according to the invention) can be administered in combination with one (or more) anticancer drugs. This treatment can be administered

Simultaneously, separately or sequentially. The treatment will be adapted by the practitioner according to the patient and the tumor to be treated.

According to a fifth aspect, the invention also relates to a method of treatment of the pathologies indicated above which includes the administration, at a patient, a dose effective of a compound according to the invention or a pharmaceutically acceptable salt thereof acceptable or hydrates or solvates.

[Examples]
The following examples illustrate the preparation of certain compliant compounds to the invention.
The numbers of the exemplified compounds refer to those given in the table below, which illustrates the chemical structures and physical properties of some compounds according to the invention.

In the examples the following abbreviations are used AcOEt: ethyl acetate MeOH: methanol DIPEA: diisopropylethylamine The compounds were analyzed by coupling HPLC-UV-MS (chromatography liquid, ultraviolet (UV) detection and mass detection). The device used is composed of

16 Agilent chromatographic system equipped with a diode array detector Agilent and a ZQ Waters single quadrupole mass spectrometer or mass spectrometer triple Quattro-MicroWaters quadrupole.

The compounds were analyzed by coupling HPLC-UV-MS (chromatography liquid, ultraviolet (UV) detection and mass detection). The device used is composed of chromatographic chain equipped with a diode array detector (HP1110 Agilent or UPLC Acquity Waters) and a quadrupole mass spectrometer (ZQ, QM or SQD
Waters).
mass spectrometry conditions Spectra of liquid chromatography / mass spectrometer (LC / MS) have been Electrospray mode (ESI) positive, to observe the ions of protonation of compounds analyzed (MH +) or the formation of adducts with other cations such as Na +, K +, etc ... The HPLC conditions are chosen from one of the methods following:
conditions TFA15 TFA3 TFA6 Symmetry C18 column (50x2,1 Acquity BEH C18 (50x2,1 mm; Acquity BEH C18 (50x2.1 mm mm; 3.5 Nm) 1.7 μm) 1.7 μm) Eluent A H2O + TFA 0.005% with H2O + TFA 0.05% at about pH H2O + TFA 0.05% at about pH
about pH 3.1 3.1 / CH3CN (97/3) 3.1 / CH3CN (97/3) Eluent B CH3CN + TFA 0.005% CH3CN + TFA 0.035% CH3CN + TFA 0.035%
Gradient 100: 0 (0 min) 10:90 100: 0 or 99: 1 (0 min) 5:95 100: 0 or 99: 1 (0 min) 5:95 A: B (10 min) 10:90 (15 (2.3 min) 5:95 (2.9 min) (4.8 min) 5:95 (6 min) min) 100: 0 (16 min) 100: 0 or 99: 1 (3 min) 100: 0 100: 0 or 99: 1 (6.1 min) 100: 0 (20 min) or 99: 1 (3.5 min) 100: 0 or 99: 1 (6.6 min) T.column 30 C 40 C 40 C
Flow rate 0.4 ml / min 1 ml / min 1 ml / min Detection A = 220 nm X = 220 nm X = 220 nm TFA: trifluoroacetic acid NMR conditions The 1 H NMR spectra are recorded on a Bruker Avance 250 spectrometer.
Bruker Advance 400 or Bruker Avance II 500. The central peak of DMSL-d6 (2.50 ppm) is in use as an internal reference. The following abbreviations are used: s:
singlet; d: doublet;
dd: double doublet; t: triplet; q: quadruplet; m: massive / multiplet;
br.s: wide signal.

17 Example 1 6- {4- [3- (6-amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino N- (2-piperidin-1-yl-ethyl) -nicotinamide (Compound No. 1 prepared according to Scheme 2) OH OH HN'D OÇ HN, __N
GN 'G CI N NHEt GN NHEt HzN FN' NHEt 0 0 -eB
HZN
HN, N
F
bocN HN-iN O
tioc ~ OON NHEt ON NH And NH
uH F
i N / N HiN N //
HHF
BOCN N

1.1. 6-chloro-2-ethylamino-nicotinic acid In a flask, mix 26.1 g (0.136 M) of 2,6-dichloro-nicotinic acid and 180 mL of aqueous 70% ethylamine solution. Stir at room temperature (RT) during 5 days.
Evaporate under reduced pressure (PR). Take up the residue with 100 mL of water.
Cool by a ice bath and acidify to pH 3 with 5N HCl solution. Filter the precipitated wash with cold water and dry under vacuum over P 2 O 5 at 60 ° C. 24.93 g (91.4%) is obtained.
of white solid.
Mp = 157-159C.

1.2. 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide In a flask, dissolve 5.0 g (24.92 mM) of 6-chloro-2-ethylamino acid nicotinic in 300 mL of THF. Add 10.41 mL (74.77 mM) of triethylamine and then 7.08 mL
(49.84 mM) 1- (2-aminoethyl) piperidine and then 11.02 g (24.92 mM) BOP. Shake at TA
during 15 hours.
Evaporate the solvent and take up the residue with ethyl acetate. Wash the organic phase with water and saturated NaCl solution. Dry on Na2SO4, filter and evaporate. The residue is purified by flah chromatography (gradient DCM-MeOH 1 to 10%). We gets 7.5 g (rdt: 96.8%) LCMS: M + 310, tr (retention time) = 1.01 min.

1.3. 6- (4-amino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide In 1 liter tricolor, add 5 g (16.1 mmol) of 6-chloro-2-ethylamino N- (2-piperidin-1-yl-ethyl) -nicotinamide. Add 4-amino-3-fluorophenylboronic acid pinacol ester (1.1 eq, 4.2 g), 300 ml of 1,2-dimethoxyethane, 60 ml of ethanol and 120 ml of a solution of NaHCO3 saturated. Incubate argon for 15 minutes, then add palladium tetrakis Pd (PPh) 4 (0.1 eq, 1.86 g). Heat at reflux (-100 C) for 16 h. Concentrate, resume in DCM, wash with H2O 2 times, H2O / NaCl, dry over sodium sulfate and concentrate.
chromatography flash on silica column 400 g, DCM / methanol gradient 99/1 up to 90/10.
We obtain 4.8

18 78%) of 6- (4-amino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl);
ethyl) -nicotinamide. LCMS (TFA3): MH + 386, tr = 0.90 min.

1.4. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide o \ NN
H
ON NH
NI ~, N
HHF

In 1 liter flask, dissolve 3.5 g (9.1 mmol) of 6- (4-amino-3-fluorophenol) phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide in 300 ml of anhydrous THF.
Add the DMAP (1.2 eq, 1.33 g) as well as N, N'-disuccinimidyl carbonate ([74124-79-1], 1.2 eq, 2.8 g). Stir at RT for 5 h. Add triethylamine (3 eq, 3.8 ml) and the 2- (di-boc-amino) -5- (aminomethyl) pyridine (1.2 eq, 3.53 g) and stir at RT overnight.
Focus.
Take up with DCM, wash with H2O 2 times, H2O / NaCl, dry and concentrate.
Flash chromatography on silica, gradient DCM / MeOH 95/5 up to 79/20 + 1%

20%. After concentration, take up the fraction thus obtained in 200 ml of DCM, then add cold 35 mL (50 eq) of TFA. Stirring at RT until the disappearance of product di-boc-amino. Concentrate and then resume the residue with 10% Na2CO3 solution.
Extract the organic phase with DCM, concentrate. Hot crystallization in acetate ethyl. Filter, rinse with AcOEt, dry in an oven. We obtain 3 g (yield = 63%) of 6- {4- [3- (6-amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide.
LCMS (TFA3): MH + 535, tr = 0.79 min; 1H NMR (250 MHz, DMSO-d6) δ ppm 1.22 (t, 3 H), 1.29 - 1.68 (m, 6H), 2.26 - 2.47 (m, 6H), 3.28 -3.42 (m, 2H), 3.43 - 3.62 (m, 2H), 4.13 (d, 2) H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), H), 7.79 - 8.07 (m, 4H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.49 (s, 1H). PF (melting point) = 175-177 C.

Example 2: 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -2-ethylamino N- (2-hydroxyethyl) -nicotinamide (Compound No. 8 prepared according to Scheme 1) 2.1. 6-chloro-2- (ethylamino) -N- (2-hydroxyethyl) nicotine HN'- OH
O
CI N NI H

Dissolve 0.5 g (2.49 mM) of 6-chloro-2- (ethylamino) nicotinic acid in 30 mL of THF.
Add 1.04 mL (0.76 mM) of triethylamine, 0.304 g (4.98 mM) of 2-hydroxyethylamine and

19 1.10 g (2.49 mM) BOP. Stir 70 hours at RT. Evaporate the solvent and take up residue by ethyl acetate; wash with water and saturated NaCl solution.
Dry on Na2SO4, filter and evaporate. Purify by chromatoflash (DCM / MeOH 1-5%). We obtain 600 mg (yield = 99%) LCMS (TFA3): MH + 244, tr = 1.03 min.
2.2. di-tert-butyl {5-f ({f2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyllcarbamoyl} amino) méthyllpyrid1n-2-yl} imidodicarbonate FBO
O
NH J- NH
NSB

O / O
X
Dissolve 5.0 g (21.09 mM) of 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and 3.09 g (25.31 mM) of DMAP (4-dimethylaminopyridine) in 500 mL of THF.
Add 6.48 g (23.31 mM) of DSC and stir at RT 18 h. Add 8.81 mL (63.27 mM) of triethylamine and 8.18 g (23.31 mM) of di-tert-butyl [5- (aminomethyl) pyridin-2-yl] imidodicarbonate. Shake at TA
5 h. Evaporate the solvent and take up the residue with DCM. Wash the phase organic with water and saturated NaCl solution. Dry on sodium sulphate, filter and evaporate.
Purify by chromatoflash. 12 g of product consisting of a 50/50 ester mixture pinacol and boronic acid. LCMS (LS) MH + 587 tr = 6.17 min and MH + 505, tr = 4.97 min.
2.3. di-tert-butylf5 - ({1 (4- {6- (ethylamino) -5-f (2-hydroxyethyl) carbamoyllpyridin-2-yl} -2-fluorophenyl) carbamoyllamino} methyl) pyrid1n-2-yllimidodicarbonate /OH
HN
O
re-OFN NH
NN
HH
N (BOC) z N
In a tricolor, place 0.3 g (1.23 mM) of the compound obtained in step 2.1, 0.794 g (1.35 mM) of compound obtained step 2.2, 15 ml of saturated solution of NaHCO3, 38 ml of DME
and 7 mL
ethanol. Degas with argon then add 0.142 g (0.12 mM) of Pd (PPh3) 4. Heat to reflux 6 h. Evaporate the solvents and take up the residue with DCM. Wash with water then saturated NaCl solution. Dry over Na2SO4, filter and evaporate. Purify by chromatoflash (DCM / MeOH 0-15%). 600 mg (yield = 73%) LCMS (TFA3): MH + 668, tr = 1.44 min.

2.4. 6- {4-I3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -2-ethylamino-N- (2-hydroxy-ethyl) -nicotinamide HN-- ~ OH
O

OF -'N NH
NH NH
H, NIN
Dissolve 0.6 g (0.9 mM) of the compound obtained in step 2.3 in 20 mL of DCM.
Cool by an ice bath and add 2.08 mL (27 mM) of TFA. Shake 18 h at RT.
Evaporate solvents and take up the residue with Na2CO3 solution. Filter, rinse with water and dry in the oven on P205. We obtain 200 mg (yield = 47.6%) LCMS (TFA3): MH + 468, tr = 0.72 min; 1H
NMR (250 MHz, DMSO-d6) δ ppm 1.22 (t, 3H), 3.31 (s, 2H), 3.43 - 3.62 (m, 4) H), 4.13 (d, 2 H, 4.71 (t, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1 H), 7.35 (dd, 1H), 7.78 -7.98 (m, 3H), 8.01 (d, 1H), 8.28 (t, 1H), 8.34-8.47 (m, 2H), 8.49 (d, 1 H).

Example 3 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide (Compound No. 15 prepared according to Scheme 3) 3.1. 6- (4- {I ({6-Ibis (tert-butoxycarbonyl) aminolpyridin-3-yl} methyl) carbamoyllamino} -3-fluorophenyl) -2- (ethylamino) nicotinic acid OH
4 I ~ O
OFN NH
X NH% IIINH

NSB
Olk, O
X
In a tricolor place 1.2 g (5.98 mM) of 6-chloro-2-(Ethylamino) nicotinic acid, 3.86 g (6.58 g) mM) di-tert-butyl {5 - [({[2-fluoro-4- (4,4,5,5-tetramethyl) -1,3,2-dioxaborolan

(Yl) phenyl] carbamoyl) amino) methyl] pyridin-2-yl} imidodicarbonate, 80 mL of DME, 15 mL
ethanol and 40 mL of saturated NaHCO3 solution. Degas with argon then heat to reflux 18 h. Evaporate the solvents and take up the residue with water.
Filter, rinse with water and dry in an oven on P205. Purify by DCM / MeOH chromatoflash 1-20%.
We obtain 1.8 g of mixture of mono compound and di-Boc. LCMS (LS) MH + 525 tr = 4.60 min and MH + 625 tr = 5.59 min.

21 3.2. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide HN, NN
-O
OF ~ 0 N NH

Dissolve 0.2 g (0.32 mM) of the compound obtained in step 3.1 in 30 mL of THF.
Add 0.115 g (0.64 mM) 2-azepan-1-ylethanamine hydrochloride, 0.18 mL (0.13 mM) triethylamine and 0.142 g (0.32 mM) BOP. Shake 18 h at RT. Evaporate, take back the residue by DCM, wash with water and saturated NaCl solution. Dry on Na2SO4, filter and evaporate. Purify by chromatoflash DCM / MeOH 0-10%. 0.250 g of mix of mono and diBoc. Dissolve this product in 15 mL DCM, cool with a bath of ice and add 0.5 mL of TFA. Shake 18 h at RT. Evaporate and take up the residue a solution Na2CO3. Filter the precipitate, wash with water and dry in an oven on P205. We gets 0.13 g (yield = 74%) LCMS (TFA3) MH + 549, tr = 0.85 min; tH NMR (400 MHz, DMSO-d6) 8 ppm 1.22 (t, 3H), 1.56 (m, 8H), 2.67 (m, 6H), 3.32 (m, 2H), 3.45 - 3.63 (m, 2H) , 4.13 (d, 2H), 5.84 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.83 (d, 1H), -8.00 (m, 4H), 8.27 (t, 1 H), 8.35 (t, 1H), 8.41 (t, 1H), 8.49 (s, 1H).

Example 4 6- {4-f (E) -3- (6-amino-pyridin-3-yl) -acryloylaminol-3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (compound No. 43 prepared according to Figure 8) NOT
NH N ' NOT
HN ^ ~
\ O + ci O
I i N NH O
NIN
HZN
F

Br HN '- "/ N
HZN NI \ O

OI \ N NH
Pd (OAc) Z
NOT
P (o-tolyl) 3 H
F
HZN N

WO 2010/1091

22 PCT / FR2010 / 050511 4.1. 6- (4-acrylamido-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-YI
ethyl) -nicotinamide Dissolve 0.385 g (lmM) of the compound obtained in step 1.3 in 20 mL of DCM;
add 0.28mL (2mM) triethylamine and 0.131g (1.1mM) DMAP followed by 0.2mL (2.2mM) chloride acryloyl. Stir at room temperature 18H. Evaporate the solvents and take back the residue by DCM. Wash with Na2CO3 solution and saturated NaCl solution.
Dry on sodium sulfate, filter and evaporate the filtrate. The residue is purified by chromatoflash (DCM -DCM / CH3OH / NH4OH 20% 95/5 / 0.2). 0.195 g (44.4%) is obtained.
LCMS (TFA3) MH + 440, tr = 2.44 min.
4.2 6- {4-f (E) -3- (6-amino-pyridin-3-yl) -acryloylaminol-3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide Dissolve 0.187 g (0.43 mM) of the compound obtained in step 4.1 in 15 mL of propionitrile;
add 0.074g (0.43mM) of 2-amino-5-bromo pyridine and 0.11mL (0.64mM) of DIPEA.
Degas with argon for 30 minutes then add 0.01g (0.04mM) of Pd (OAc) 2 and 0.022 g (0.07 mM) of tri-orthotolyl phosphine. Bring to reflux 3H. After return at temperature Ambient dilute with DCM and filter on Whatman. Evaporate the filtrate and purify the residue by DCM - DCM / CH3OH / NH4OH chromatoflash 20% 85/15 / 0.2. 0.120 g (53%) is obtained.

Example 5: 2-Ethylamino-6- [3-fluoro-4 - ((E) -3-pyridin-3-yl-acryloylamino) phenyl] -N- (2 piperidin-1-yl-ethyl) -nicotinamide (Compound No. 44) HN N
HN - IN O
OO
O-NH
N NH + j ci NOT
NHF

F
Dissolve 0.25 g (0.65 mM) of the compound obtained in step 1.3 in 20 mL of DCM and add 0.27mL (1.95mM) of triethylamine. Cool the reaction medium with a bath of ice and add dropwise 0,163g (0,97mM) of (E) -3-pyridin-3-yl-acryloyl chloride. Shake to room temperature 18H. Wash the organic solution with NaOH solution 10%, dry on Na2SO4, filter and evaporate the filtrate. Purify the residue by chromatoflash Si02 C18 CH3OH / H2O 50/50 - 90/10. 0.035 g (10.4%) is obtained.

23 Example 6: 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino N- [2- (1-oxy-piperidin-1-yl) -ethyl] -nicotinamide (Compound No. 45) HNHN
o MCPBA o IOI N 'NH ON NIH
HH FH ~ HF

NOT
HN- I
O
TFA o ON NH
H
-LINEN
HzN N
6.1 5β- (4- {6-Ethylamino-5-β- (1-oxy-piperidin-1-yl) -ethylcarbamoyll-pyridin]

2-fluoro-phenyl) -ureidomethyll-pyridin-2-yl} -carbamic acid tert-butyl ester Put 0.35g (0.55mM) of [5- (3- {4- [6-ethylamino-5- (2-piperidin-1-yl)}
ethylcarbamoyl) -pyridin 2-yl] -2-fluoro-phenyl} -ureidomethyl) -pyridin-2-yl] -carbamic acid tert-butyl suspended ester in 35mL DCM and 10mL of CHC13. Cool by an ice bath and add 0,105g (0.61 mM) chloro-perbenzoic meta acid. Shake 0,5H cold then 2H to temperature room. Wash the organic phase with a NaHCO3 solution then H2O then a solution saturated NaCl. Dry on Na2SO4, filter and evaporate. The residue is purified by chromatoflash on A1203 neutral DCM / CH3OH - 98/2 to 92/8.
0.340 g (94.7%) is obtained.
LCMS (TFA3) MH + 651, tr = 2.07 min.

6.2 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureidol-3-fluoro-phenyl} -2-ethylamino-N-2- (1-oxy-piperidin-1-yl) -ethyl-nicotinamide Dissolve 0.328 g (0.5 mM) of the compound obtained in step 6.1 in 20 mL of CH 2 Cl 2.
Cool with an ice bath and add 0.85mL (11.1 mM) TFA. Shake to temperature ambient 44H. Evaporate and take up the residue with 10% Na2CO3 solution and extract DCM. Dry on Na2SO4, filter and evaporate. The residue is purified by chromatoflash on

24 A1203 neutral DCM / CH3OH - 95/5 to 88/12. 0.213 g (76.9%) is obtained.
1H NMR of the compounds of Table 1 Chemical shifts are given in ppm.
Compound No. 2: (400MHz) 1.22 (t, 3H), 1.35-1.81 (m, 6H), 2.54-3.16 (m, 6H);
H), 3.45 -3.57 (m, 4H), 4.13 (d, 2H), 5.88 (s, 2H), 6.44 (d, 1H), 7.02-7.14 (m, 2H), 7, 35 (dd, 1H), 7.85 - 7.92 (m, 2H), 7.98 (d, 1H), 8.16 (dd, 1H), 8.35 (t, 1H), 8.61 (brs, 1H), 8.75 (s, 1H).

Compound No. 3: (250 MHz) 1.22 (t, 3H), 1.32 - 1.60 (m, 6H), 2.40 - 2.65 (m, 6) H), 3.29 -3.46 (m, 2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1 H), 7.35 (dd, 1H), 7.88 (d, 1H), 8.00 - 8.19 (m, 2H), 8.25 - 8.39 (m, 1H), 8.50 - 8.63 (m, 2H), 8.68;
(s, 1H), 8.75 (t, 1H).
Compound No. 4: (250 MHz) 1.22 (t, 3H), 1.32 - 1.60 (m, 6H), 2.40 - 2.65 (m, 6) H), 3.29 -3.46 (m, 2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1 H), 7.35 (dd, 1H), 7.88 (d, 1H), 8.00 - 8.19 (m, 2H), 8.25 - 8.39 (m, 1H), 8.50 - 8.63 (m, 2H), 8.68;
(s, 1H), 8.75 (t, 1H).
Compound No. 5: (250 MHz) 1.28 - 1.65 (m, 6H), 2.32 - 2.47 (m, 6H), 3.35 -3.52 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.02 (t, 2H), 7.26-7.52 (m, 4H) , 7.75 (d, 2H), 7.82 -8.04 (m, 3H), 8.16 (d, 1H), 8.34 (t, 1H), 8.53 (s, 1H), 8.69 (t, 1H), 11.06 (s, 1H).
Compound No. 6: (250 MHz) 0.97 (d, 6H), 1.21 (t, 3H), 1.57 (br s, 1H), 2.58-2.87 (m, 3H), 3.23 3.34 (m, 2H), 3.43 - 3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 2H), , 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.80-8.10 (m, 4H), 8.28 (t, 1H), 8.34-8.48 (m.p. , 2H), 8.51 (d, 1H).

Compound No. 7: (250 MHz) 1.22 (t, 3H), 2.66 (t, 2H), 2.89-3.17 (m, 8H), 3.31 - 3.42 (m, 2H), 3.45 - 3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1 H), 7.17 (d, 1H), 7.35 (dd, 1H), 7.83-8.03 (m, 4H), 8.28 (t, 1H), 8.34-8.46 (m, 2H), 8.50 (d, 1H), , 1H).

Compound No. 9: (250 MHz) 0.49 - 0.60 (m, 2H), 0.77 - 0.94 (m, 2H), 1.29 -1.57 (m, 6H), 2.28 -2.48 (m, 6H), 2.99 - 3.11 (m, 1H), 3.31 - 3.42 (m, 2H), 4.13 (d, 2H), 5, 83 (s, 2H), 6.44 (d, 1) H), 7.03 (t, 1H), 7.36 (dd, 1H), 7.88 (d, 1H), 8.05 - 8.23 (m, 2H), 8.28; -8.38 (m, 1H), 8.50 -8.64 (m, 2H), 8.69 (s, 1H), 8.77 (d, 1H).

Compound No. 10: (250 MHz) 1.27 - 1.70 (m, 6H), 2.49 - 2.87 (m, 6H), 3.40 -3.58 (m, 2H), 4.14 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.07 (t, 1H), 7.15 (t, 1H), 7.36 (d, 1H), (dd, 1H), 7.40 - 7.50 (m, 2 H), 7.77 (d, 2H), 7.88 (d, 1H), 8.03 (dd, 1H), 8.13 (dd, 1H), 8.38 (t, 1);
H), 8.63 (d, 1H), 8.81 -9.04 (m, 2H), 11.15 (s, 1H).

Compound No. 11: (250 MHz) 1.20 (t, 3H), 1.29 - 1.66 (m, 6H), 2.11-2.47 (m, 6H), 3.25 -3.40 (m, 2H), 3.42 - 3.62 (m, 2H), 4.11 (d, 2H), 5.76 (s, 2H), 6.43 (d, 1H). , 6.61 (br s, 1 h), 6.97 (d, 1H), 7.12 (d, 1H), 7.35 (d, 1H), 7.62 (d, 1H), 7.77 - 8.05 (m, 3H) , 8.28 - 8.48 (m, 2H), 8.91 (s, 1H).

Compound No. 12: (250 MHz) 1.22 (t, 3H), 1.57-1.86 (m, 4H), 2.43 - 2.52 (m, 4H), 2.57 (t, 2H), 3.29 - 3.43 (m, 2H), 3.43 - 3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6, 44 (d, 1H), 6.99 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.80 - 8.04 (m, 4H), 8.28 (t, 1H), 8.35 -8.48 (m, 2H), 8.51 (brs), 1H).
Compound No. 13: (250 MHz) 1.22 (t, 3H), 2.75 (d, 3H), 3.43 - 3.66 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.82 (d, 1H), -8.04 (m, 4H), 8.28 (t, 1) H), 8.35-8.62 (m, 3H).

Compound No. 14: (250 MHz) 1.22 (t, 3H), 3.27 (s, 3H), 3.35 - 3.62 (m, 6H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.37 (dd, 1H), 7.82 (d, 1H), -8.07 (m, 4H), 8.28 (t, 1 H), 8.50 (brs, 3H).

Compound No. 16: (400 MHz) 1.22 (t, 3H), 2.56 (t, 2H), 2.66 - 2.75 (m, 4H), 2.82 - 3.04 (m, 4H), 3.34 - 3.41 (m, 2H), 3.45 - 3.60 (m, 2H), 4.13 (d, 2H), 5.87 (s, 2H), 6, 44 (d, 1H), 6.99 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.82-7.99 (m, 4H), 8.27 (t, 1H), 8.34-8.47 (m, 2H), 8.50 (d, 1) H).

compound no. 17: (250 MHz) 1.22 (t, 3H), 1.29 - 1.62 (m, 6H), 2.04 (s, 3H), 2.29 - 2.47 (m, 6H), 3.30 - 3.41 (m, 2H), 3.44 - 3.60 (m, 2H), 4.13 (d, 2H), 5.62 (s, 2H), 6, 96 (t, 1H), 7.16 (d, 1H), 7.22 (s, 1H), 7.76 (s, 1H), 7.82-8.06 (m, 3H), 8.28 (t, 1H), 8.33-8, 46 (m, 2H), 8.48 (d, 1H).
compound no. 18: (250 MHz) 0.32 - 0.57 (m, 1H), 0.78 (d, 6H), 1.18 (t, 3H), 1.35 - 1.70 (m, 5H), 2.39 (t, 2H), 2.79 (d, 2H), 3.22 - 3.38 (m, 2H), 3.41 - 3.56 (m, 2H), 4, 09 (d, 2H), 5.78 (s, 2H), 6.39 (d, 1H), 6.92 (t, 1H), 7.11 (d, 1H), 7.30 (dd, 1H), 7.74-7.98 (m, 4 H), 8.23 (t, 1H), 8.28 -8.42 (m, 2H), 8.44 (d, 1H).

compound n 19: (250 MHz) 1.11 (d, 6H), 1.02 - 1.32 (m, 3H), 1.21 (t, 3H), 1.39 - 1.73 (m, 3H), 2.37 - 2.51 (m, 2H), 2.59 - 2.78 (m, 2H), 3.11 - 3.29 (m, 2H), 3.42 - 3.59 (m, 2H), 4.13 (d, 2) H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), H), 7.83 - 8.01 (m, 4H), 8.28 (t, 1H), 8.35-8.59 (m, 3H).

Compound No. 20: (250 MHz) 0.94 - 1.13 (m, 4H), 1.22 (t, 3H), 1.30 - 1.68 (m, 6H), 2.41 -2.65 (m, 6H), 3.31 - 3.68 (m, 4H), 5.70 (s, 2H), 6.43 (d, 1H), 6.67 (brs), 1 H), 7.16 (d, 1H), 7.29 (d, 1H), 7.73-8.07 (m, 4H), 8.19-8.34 (m, 1H), 8.42 (br.s, 2H), 8, 54 (s, 1H).

Compound No. 21: (250 MHz) 1.13 (t, 3H), 1.27 - 1.69 (m, 6H), 2.16 - 2.47 (m, 6H), 3.32-3.43 (m, 4H), 4.11 (d, 2H), 5.81 (s, 2H), 6.43 (d, 1H), 6.61-6.82 (m, 2H) , 7.23 (d, 2H), 7.35 (d, 1H), 7.87 (s, 1H), 7.92 (d, 1H), 8.27 (brs, 1H), 8.41 (br.s, 1H), 9.03 (s, 1H).

Compound No. 22: (250 MHz) 1.19 (t, 3H), 1.30 - 1.64 (m, 6H), 2.31 - 2.50 (m, 6H), 3.32-3.42 (m, 2H), 3.41 - 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H) , 6.89 - 7.06 (m, 2H), 7.35 (dd, 1H), 7.70-7.83 (m, 1H), 7.88 (d, 1H), 7.96 (d, 1H), 8.09 (t, 1 H), 8.35 (t, 1H), 8.43 (t, 1H), 8.67 (d, 1H).

Compound No. 23: (250 MHz) 1.22 (t, 3H), 1.33-1.68 (m, 6H), 2.52-2.92 (m, 6H) H), 3.15 -3.27 (m, 2H), 3.34 - 3.50 (m, 2H), 4.12 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H) , 6.80 - 6.90 (m, 2H), 6.94 (t, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7.52-7.66 (m, 2H), 7.78-7, 93 (m, 2H), 8.13 - 8.37 (m, 2H), 8.43 (d, 1H).

Compound No. 24: (250 MHz) 0.39 - 0.51 (m, 2H), 0.51 - 0.59 (m, 2H), 0.59 -0.75 (m, 2H), 0.75 0.90 (m, 2H), 2.68 - 2.86 (m, 1H), 2.86 - 3.09 (m, 1H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1) H), 6.98 (t, 1H), 7.21 (d, 1H), 7.35 (dd, 1H), 7.83-8.13 (m, 4H), 8.29;
(t, 1H), 8.38 - 8.65 (m, 3 H).

Compound No. 25: (250 MHz) 0.35 - 0.55 (m, 2H), 0.69 - 0.84 (m, 2H), 1.41 -2.01 (m, 8H), 2.85 3.05 (m, 1H), 4.13 (d, 2H), 4.13-4.26 (m, 1H), 5.83 (s, 2H), 6.44 (d, 1H); , 1H), 6.98 (t, 1H), 7.22 (d, 1H), 7.35 (dd, 1H), 7.84-8.08 (m, 4H), 8.22-8.37 (m, 2H), 8.44-8.57 (m, 2H) Compound No. 26: (250 MHz) 0.37 - 0.55 (m, 2H), 0.71-0.83 (m, 2H), 0.89 (t, 3) H), 1.18 -1.41 (m, 2H), 1.41 - 1.63 (m, 2H), 2.84 - 3.05 (m, 1H), 3.21 (q, 2H), 4.13 (d, m.p. , 2H), 5.86 (s, 2H), 6.45 (d, 1H), 6.98 (t, 1H), 7.23 (d, 1H), 7.36 (dd, 1H), 7.83-8.09 (m, 4 H), 8.29 (t, 1H), 8.39 -8.68 (m, 3H) Compound No. 27: (250 MHz) 1.22 (t, 3H), 1.29 - 1.58 (m, 6H), 2.28 - 2.47 (m, 6H).
H), 3.30 -3.41 (m, 2H), 3.43 - 3.62 (m, 2H), 4.37 (d, 2H), 7.16 (d, 1H), 7.23 (t, 1H); , 7.39 (dd, 1H), 7.69 -7.79 (m, 1H), 7.82 - 8.03 (m, 3H), 8.26 (t, 1H), 8.31 - 8.46 (m, 2H), 8, 49 (dd, 1H), 8.56 (d, 1) H), 8.64 (d, 1H).

compound no. 28: (250 MHz) 1.22 (t, 3), 1.23 - 1.6 (m, 6), 2.30 - 2.50 (m, 6), 2.75 (d, 3), 3.34 (m, 2), 3.52 (which, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6.98 (t, 1), 7, 16 (d, 1), 7.37 (dd, 1), 7.80 - 8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).

compound 29: (250 MHz) 1.22 (t, 3H), 1.29 - 1.60 (m, 6H), 2.31 - 2.47 (m, 6H), 3.00 (s, 6H), 3.26 - 3.42 (m, 2H), 3.45 - 3.60 (m, 2H), 4.18 (d, 2H), 6.64 (d, 1H), 7, 01 (s, 1H), 7.16 (d, 1H), 7.49 (dd, 1H), 7.81-8.01 (m, 3H), 8.06 (d, 1H), 8.28 (t, 1H), 8.33 -8.46 (m, 2H), 8.51 (d, 1H) compound 30: (250 MHz) 1.22 (t, 3H), 1.30 - 1.63 (m, 6H), 2.29 - 2.47 (m, 6H), 3.29 -3.40 (m, 2H), 3.44 - 3.63 (m, 2H), 4.22 (d, 2H), 5.32 (s, 2H), 6.86 (s, 1H). , 7.03 - 7.22 (m, 2H), 7.71 (s, 1H), 7.79-8.02 (m, 4H), 8.28 (t, 1H), 8.33-8.51 (m, 2H), 8, 58 (s, 1H) Compound No. 31: (500 MHz) 1.23 (t, 3H), 1.34 - 1.43 (m, 2H), 1.45 - 1.57 (m, 4H), 2.31 -2.49 (m, 6H), 3.31 - 3.39 (m, 2H), 3.46 - 3.59 (m, 2H), 4.43 (d, 2H), 7.17 (d, 2H), , 1H), 7.27 (t, 1H), 7.62 -7.76 (m, 1H), 7.88 (dd, 1H), 7.91-8.02 (m, 2H), 8.24 (t, 1H), 8.38 (t. , 1H), 8.42 (t, 1H), 8.46 (t, 1H), (s, 1H), 8.49 (d, 1H), 8.69 (d, 1H) Compound No. 32: (400 MHz) 1.22 (t, 3H), 1.33 - 1.61 (m, 6H), 2.31 (s, 3H), 2.51 (s, 6H), 3.34 -3.43 (m, 2H), 3.46 - 3.60 (m, 2H), 4.34 (d, 2H), 7.16 (d, 1H), 7.21 (t, 1 H), 7.54 (s, 1H), 7.87 (d, 1H), 7.90 - 8.05 (m, 2H), 8.21 - 8.29 (m, 1H), 8.29 - 8.37 (m, 2H), 8.37 -8.49 (m, 2H), 8.62 (d, 1H) Compound No. 33 (250 MHz) 1.22 (t, 3H), 1.31 - 1.59 (m, 6H), 2.22 - 2.47 (m, 6H).
H), 3.29-3.41 (m, 2H), 3.53 (m, 2H), 5.67 (s, 2H), 6.45 (d, 1H), 7.17 (d, 1H), 7.51 (dd, 1 H), 7.80 - 8.05 (m, 4H), 8.27 (t, 1H), 8.41 (d, 2H), 8.70 (br.s, 2H).

Compound No. 34: (400 MHz) 1.22 (t, 3H), 1.40 (d, 2H), 1.53 (quin, 4H), 2.41 -2.60 (m, 6H), 2.45 (s, 3H), 3.34 - 3.42 (m, 2H), 3.47 - 3.57 (m, 2H), 4.32 (d, 2H), 7.11 -7.21 (m, 2H), 7.23 (d, 1H), 7.61 (dd, 1H), 7.87 (d, 1H), 7.90 - 8.03 (m, 2H), 8.25 (t, 1H), 8, 41 (s, 3H), 8.60 (d, 1H) Compound No. 35: (400 MHz) 1.22 (t, 3H), 1.32 - 1.45 (m, 2H), 1.64 - 1.78 (m, 2H), 2.06 (t, 2H), 2.43 (t, 2H), 2.64 - 2.77 (m, 2H), 3.32 (s, 2H), 3.37 - 3.48 (m, 1H), 3, 48 - 3.57 (m, 2H), 4.13 (d, 2H), 4.52 (d, 1H), 5.83 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), d, 1H), 7.34 (dd, 1H), 7.86 (d, 2H), 7.89-7.99 (m, 2H), 8.27 (t, 1H), 8.33-8.45 (m, 2H), 8.49 (d. , 1 H) Compound No. 36: (250 MHz) 0.94 - 1.15 (m, 1H), 1.22 (t, 3H), 1.30 - 1.52 (m, 1H), 1.52 -1.69 (m, 1H), 1.69 - 1.97 (m, 3H), 2.44 (t, 2H), 2.62 - 2.77 (m, 1H), 2.85 (dd , 1H), 3.28 - 3.39 (m, 2H), 3.39 - 3.62 (m, 3H), 4.13 (d, 2H), 4.56 (d, 1H), 5.83 (s, 2H), 6.44;
(d, 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.82-8.03 (m, 4H), 8.28 (t, 1H), 8.33-8.46;
(m, 2H), 8.51 (d, 1H) Compound No. 37: (400 MHz) 0.99 (d, 12), 1.22 (t, 3), 2.51 (m, 2), 2.99 (m, 2), 3.19 (q, 2), 3.53 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (s, 2), dd, 1), 7.80 - 8.00 (solid, 4);
8.27 (t, 1), 8.37 (t, 1), 8.42 - 8.54 (bulk, 2) Compound No. 38: (400 MHz) 1.22 (t, 3), 1.40 (m, 2), 1.82 (m, 2), 2.12 (t, 2), 2.44 (t, 2), 2.72 (m, 2), 3.15 (sep, 1), 3.22 (s, 3), 3.32 (m, 2), 3.52 (which, 2), 4.15 (d, 2), 5, 84 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80-8.00 (m, 4), 8.27 (t, 1), 8.37 (t, 1), ) 8.40 (t, 1), 8.49 (d, 1).

compound 39: (250 MHz) 1.22 (t, 3H), 1.30 - 1.57 (m, 6H), 1.66 (t, 2H), 2.18 - 2.41 (m, 6H), 3.16 - 3.29 (m, 2H), 3.40 - 3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6, 44 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.81-8.03 (m, 4H), 8.28 (t, 1H), 8.36-.
8.58 (m, 3H).

Compound No. 40: (400 MHz) 1.22 (t, 3), 1.30 - 1.59 (m, 10), 2.23 (t, 2), 2.28 (ss, 4), 3.23 (q, 2);
3.52 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), , 1), 7.34 (dd, 1), 7.82 - 8.00 (m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (sl, 1).

compound 41: (400 MHz) 1.22 (t, 3H), 2.14 (s, 3H), 2.18-2.49 (m, 10H), 3.31 - 3.39 (m, 2 H), 3.44 - 3.58 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.43 (d, 1H), 6.97;
(t, 1H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.81 - 7.89 (m, 2H), 7.89 - 7.98 (m, 2H), 8.27 (t, 1H), 8.32 -8.45 (m, 2H), 8.49 (d, 1) H) Compound No. 42: (250 MHz) 1.22 (t, 3H), 2.02 (brs, 1H), 2.27 - 2.38 (m, 4) H), 2.41 (t, 2H), 2.62 2.74 (m, 4H), 3.22 - 3.41 (m, 2H), 3.44 - 3.59 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 7.00 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.82 - 8.02 (m, 4H), 8.28 (t, 1H), 8.33 - 8.46 (m, 2H), 8.51 (d, 1H) Compound No. 43: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (t, 3H), 1.35 - 1.44 (m, 2H), 1.51 (quin, 4H), 2.33 - 2.50 (m, 6H), 3.33 - 3.41 (m, 2H), 3.50 - 3.59 (m, 2H), 6.48 - 6.56 (m, 3H), 6.86 (d, 1H), 7.22 (d, 1H), 7.49 (d, 1H), 7.66 (dd, 1H), 7.90-8.06 (m, 3).
H), 8.16 (d, 1H), 8.31 (t, 1H), 8.41 (q, 2H), 9.88 (s, 1H).

Compound No. 44: 1H NMR (250 MHz, DMSO-d6) δ ppm 1.23 (t, 3H), 1.31 - 1.64 (m, 6H), 2.23 -2.47 (m, 6H), 3.29 -3.41 (m, 2H), 3.46 - 3.65 (m, 2H), 7.21 (s, 1H), 7.26 (d, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.93 - 8.13 (m, 4H), 8.31 (t, 1H), 8.37 - 8.47 (m, 2H), 8.62 (d, 1H), 8.85 (d, 1H), 10.17 (s, 1H).

Compound No. 45: 1H NMR (250 MHz, DMSO-d6) δ ppm 1.22 (t, 7H), 1.96 - 2.26 (m, 2H), 3.16 (d, 4H), 3.40 (t, 2H), 3.52 (ddt, 2H), 3.71 (d, 2H), 4.13 (d, 2H), 5.83 (s, 2);
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The compounds of Table I have for chemical name (obtained from the software Autonom) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-piperidin 1-yl-ethyl) -nicotinamide (Compound No. 1) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,5-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 2) 2- [4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl) -4-ethylamino pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide (n 3) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-cyclopropylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 4) N- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-phenylamino N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 5) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-isopropylamino-ethyl) -nicotinamide (n 6) 6- [4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (1,1 dioxo thiomorpholin-4-yl) -ethyl] -2-ethylamino-nicotinamide (n 7) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-hydroxy-ethyl) -nicotinamide (n 8) 2- [4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-cyclopropylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide (# 9) 2- [4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl) -4-phenylamino pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide (n 10) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2-fluoro-phenyl} -2-ethylamino-N-(2-piperidin 1-yl-ethyl) -nicotinamide (n 11) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-pyrrolidin 1-yl-ethyl) -nicotinamide (n 12) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-methyl-nicotinamide (n 13) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-methoxy-ethyl) -nicotinamide (n 14) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-azepan-1-) yl-ethyl) -2-ethylamino-nicotinamide (n 15) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (1-oxo thiomorpholin-4-yl) -ethyl] -nicotinamide (n 16) 6- {4- [3- (6-Amino-5-methyl-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (key 17) N- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2 - ((cis-3,5-dimethyl piperidin-1-yl) -ethyl] -2-ethylamino-nicotinamide (n 18) 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (cis-2,6 dimethyl piperidin-1-yl) -ethyl] -2-ethylamino-nicotinamide (# 19) 6- (4- {3- [2- (6-Amino-pyridin-3-yl) -ethyl] -ureido} -3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 20) ^ 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,6-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 21) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,3-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 22) 4 '- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-ethylamino-3'-fluoro-biphenyl-4-carboxylic acid (2-piperidin-1-yl-ethyl) -amide (n 23) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopropyl-cyclopropylamino-nicotinamide (n 24) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopentyl-cyclopropylamino-nicotinamide (n 25) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-butyl-2-cyclopropylamino-nicotinamide (n 26) 2-Ethylamino-6- [3-fluoro-4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 27) 2-Ethylamino-6- {3-fluoro-4- [3- (6-methylamino-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 28) 6- {4- [3- (6-Dimethylamino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 29) 6- {4- [3- (5-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-piperidin 1-yl-ethyl) -nicotinamide (n 30) 2-Ethylamino-6- {3-fluoro-4- [3- (5-fluoro-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 31) 2-Ethylamino-6- {3-fluoro-4- [3- (5-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin 1-yl-ethyl) -nicotinamide (n 32) N- {4- [3- (6-Aminopyridin-3-yl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 33) 2-Ethylamino-6- {3-fluoro-4- [3- (6-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin 1-yl-ethyl) -nicotinamide (key 34) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (4-hydroxy-piperidin-1-yl) -ethyl] -nicotinamide (n 35) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (3-hydroxy-piperidin-1-yl) -ethyl] -nicotinamide (N 36) N- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-diisopropylamino-ethyl) -2-ethylamino-nicotinamide (n 37) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (4-methoxy-piperidin-1-yl) -ethyl] -nicotinamide (38) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(3-piperidin 1-yl-propyl) -nicotinamide (n 39) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(4-piperidin 1-yl-butyl) -nicotinamide (n 40) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (4-methyl-piperazin-1-yl) -ethyl] -nicotinamide (n 41) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-piperazin-1-yl-ethyl) -nicotinamide (n 42) 6- {4 - [(E) -3- (6-Amino-pyridin-3-yl) -acryloylamino] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 43) 2-Ethylamino-6- [3-fluoro-4 - ((E) -3-pyridin-3-yl-acryloylamino) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 44) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-[2- (1-oxy-piperidin-1-yl) -ethyl] -nicotinamide (n 45) The compounds described in Table I have been tested pharmacological to determine the anticancer activity. They have been tested in vitro on the tumor line HCT116 (ATCC-CCL247). Proliferation and cell viability have been determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H
tetrazolium (MTS) according to Fujishita T. et al. Oncology 2003, 64 (4), 399-406.
In this test, we measures the mitochondrial capacity of living cells to transform the STD
in a compound stained after 72 hours of incubation of the test compound. Concentration compound that leads to 50% loss of proliferation and cell viability is noted IC50.
For the compounds of Table I, an IC50 <1000 nM (1 μM) on the HCT116 line.
Some compounds (eg n 1, 5, 11, 19, 27) even have <1 activity nM.

Claims (23)

1. Compound of formula (1):

in which :
.cndot. Z and Z 'are N or CH;
.cndot. x is an integer equal to 1 or 2, representing the number of atom (s) of fluoride attached to the central phenyl nucleus;
.cndot. L represents a group -CH = CH- or - (CH2) n NH - in which the group NH is attached at C = O and n is an integer of 0, 1 or 2;
.cndot. R1 represents a hydrogen atom, a (C1-C6) alkyl group, (C3-C6) cycloalkyl, phenyl;
.cndot. R1 represents a hydrogen atom or a (C1-C6) alkyl group;
.cndot. R2 represents:
a (C3-C6) cycloalkyl group;
a (C1-C6) alkyl group, optionally substituted with:
one or more hydroxy or (C1-C4) alkoxy groups;
a group -NR a R b in which R a and R b independently represent one of the other a hydrogen atom or a (C1-C6) alkyl group or together with the nitrogen atom to which they are attached a (C4-C6) heterocycloalkyl group optionally comprising in the cycle the group -S (O) q with q = 0, 1 or 2 or the -NH- or -N (C1-C4) alkyl- and being optionally substituted by one or more substituent (s), which are identical or different from each other when there are several, chosen from among group -OH ; (C1-C4) alkoxy or (C1-C4) alkyl;
.cndot. R3 represents at least one substituent of the pyridine ring chosen from an atom of hydrogen or fluorine, a (C1-C4) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (C1-C4) alkyl group. The compound of claim 1 wherein R 1 is the group cyclopropyl, or the phenyl group or a (C1-C6) alkyl group and R1 represents an atom hydrogen. 3. The compound of claim 1 wherein R'1 represents an atom hydrogen. 4. Compound according to claim 1 to 3, in which R2 represents:
cyclopropyl or cyclopentyl group;
a (C1-C6) alkyl group, optionally substituted with:
one or more -OH or (C1-C4) alkoxy group (s);

~ the pyrrolidinyl group ( ), piperidinyl ( ), piperazinyl ( ) or N- (C1-C4) alkyl-piperazinyl ( ) azepanyl ( ) thiomorpholinyl ( ), 1-oxo-thiomorpholinyl ( ) 1,1-dioxothiomorpholinyl ( ), 3-hydroxypiperidinyl ( ) or 4-hydroxy-piperidinyl ( ), 4-methoxy-piperidinyl ( ), cis-3,5-dimethyl-piperidinyl ( ) or cis-2,6-dimethylpiperidinyl ( ). 5. Compound according to one of the preceding claims wherein R3 is in position and / or 6 on the pyridine ring. 6. Compound according to one of the preceding claims wherein the number of substituents R3 is equal to 1 and / or R3 is in position 5 or 6 on the nucleus pyridine. 7. Compound according to one of claims 1 to 6 wherein R3 is -NH2. 8. Compound according to one of the preceding claims wherein n is equal to 1 or L
represents the group -CH = CH- in E or Z form. 9. Compound according to one of the preceding claims wherein Z and Z ' represent respectively N and CH; CH and CH or N and N. 10. Compound according to one of the preceding claims wherein x is 1. 11. Compound according to claim 1 of formula (I "):

wherein R1 represents a (C1-C4) alkyl group, R2 represents a group (C1 C6) alkyl optionally substituted with a group -NR a R b wherein R a and R b form together with the nitrogen atom to which they are connected the group (C4-C6) heterocycloalkyl optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C1-C4) alkyl, x is an integer of 1 or representing the number of fluorine atom (s) attached to the central phenyl ring and R3 is as defined in one of claims 1, 5 to 7. The compound of claim 11 wherein the group (C4-C6) heterocycloalkyl is selected from pyrrolidinyl, piperidinyl, piperazinyl, N- (C1-C4) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxo thiomorpholinyl, 1,1-dioxothiomorpholinyl, 3-hydroxypiperidinyl or 4-hydroxy-piperidinyl, methoxy-piperidinyl, cis-3,5-dimethyl-piperidinyl or cis-2,6-dimethyl-piperidinyl. 13. Compound according to one of claims 1 to 12 wherein x is 1 and the atom of fluorine is in position 3. 14. A compound according to any one of the preceding claims in the form of of base or an addition salt with an acid or in the form of a hydrate or a solvate. The compound of claim 1 selected from one of the following:

.cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin 1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,5-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 2- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-ethylamino-pyrimidin-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-cyclopropylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-phenylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-isopropylamino-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2-(1,1-dioxo thiomorpholin-4-yl) -ethyl] -2-ethylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-hydroxy-ethyl) -nicotinamide .cndot. 2- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-cyclopropylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide .cndot. 2- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-phenylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2-fluoro-phenyl} -2-ethylamino-N- (2-piperidin 1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-pyrrolidin 1-yl-ethyl) - nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-methyl-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-methoxy-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxo thiomorpholin-4-yl) -ethyl] -nicotinamide .cndot. 6- {4- [3- (6-Amino-5-methyl-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2-((Cis-3,5-dimethyl-piperidin-1-yl) -ethyl] -2-ethylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2-(Cis-2,6-dimethyl-piperidin-1-yl) -ethyl] -2-ethylamino-nicotinamide .cndot. 6- (4- {3- [2- (6-Amino-pyridin-3-yl) -ethyl] -ureido} -3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,6-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,3-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 4 '- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-ethylamino-3'-fluoro biphenyl-4-carboxylic acid (2-piperidin-1-yl-ethyl) -amide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopropyl-2-cyclopropylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopentyl-2-cyclopropylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-butyl-2-cyclopropylamino-nicotinamide .cndot. 2-Ethylamino-6- [3-fluoro-4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -N- (2 piperidin-1-yl-ethyl) -nicotinamide .cndot. 2-Ethylamino-6- {3-fluoro-4- [3- (6-methylamino-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Dimethylamino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (5-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin 1-yl-ethyl) -nicotinamide .cndot. 2-Ethylamino-6- {3-fluoro-4- [3- (5-fluoro-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 2-Ethylamino-6- {3-fluoro-4- [3- (5-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin 1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-yl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-(2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 2-Ethylamino-6- {3-fluoro-4- [3- (6-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin 1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-hydroxy-piperidin-1-yl) -ethyl] -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (3-hydroxy-piperidin-1-yl) -ethyl] -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-diisopropylamino-ethyl) -2-ethylamino-nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methoxy-piperidin-1-yl) -ethyl] -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (3-piperidin 1-yl-propyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (4-piperidin 1-yl-butyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methyl-piperazin-1-yl) -ethyl] -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperazin-1-yl-ethyl) - nicotinamide .cndot. 6- {4 - [(E) -3- (6-Amino-pyridin-3-yl) -acryloylamino] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 2-Ethylamino-6- [3-fluoro-4 - ((E) -3-pyridin-3-yl-acryloylamino) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide .cndot. 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxy-piperidin-1-yl) -ethyl] -nicotinamide in the form of a base or an acid addition salt or in the form of a hydrates or of a solvate. 16. Compound of formula:

in which L represents a group -CH = CH- or- (CH2) n-NH- in which group NH is attached to C = O, R3 is as defined in claim 1, 5 to 7 and K
and K ' represent a hydrogen atom, an alkyl or aryl group, optionally connected between them to form together with the boron atom and the two atoms oxygen a 5- to 7-membered ring optionally substituted by at least one group (C1-C4) alkyl or to which is optionally attached to two carbon atoms consecutive of said cycle a phenyl group. 17. Compound according to claim 13, characterized in that -B (OK) (OK ') represent one of the following groups:
18. Formula compound or formula wherein R 1, R 1, R 2, R 3, Z, Z 'and x are as defined in one of Claims 1 to 10. 19. Medicinal product characterized in that it comprises a compound according to one of the Claims 1 to 15. 20. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 15 and at least one excipient pharmaceutically acceptable. 21. Compound according to claim 1 to 15 as anti-cancer agents. 22. Use of a compound according to one of claims 1 to 15 for the manufacture of a medicament for the treatment or prevention of cancer. 23. Use of a compound selected from the following list:

as an intermediate in the preparation of a compound as defined in one of Claims 1 to 15.